Summary of work: The aim of this project is to assess the effects of aging at a behavioral level of analysis, to identify neurobiological mechanisms associated with these effects, and to evaluate interventions that might alter age-related performance decrements. Rodent models are tested in a battery of sensorimotor and learning/memory tasks. Neurochemical and neurohistological assays are conducted to determine neurobiological correlates of functional losses. Interventions include dietary restriction, various pharmacologic treatments, and gene transfer via adenoviral vectors. Multiple genotypes are examined to determine possible genetic involvement in the pattern of age-related behavioral impairment. We have identified various effective pharmacologic strategies for improving learning performance of aged rats using manipulations of the cholinergic and glutamatergic neurotransmitter systems of great current interest is the improved learning of aged rats treated with a combination of drugs stimulating glycine polyamine receptors. In addition, specific inhibitors of butylcholinesterase also appear to have cognitive enhancing effects. Use of nitric oxide generating compounds has also proven to be a successful strategy for cognitive enhancement in aged rats. We are also examining inflammatory responses in the aged brain and have noted enhanced cytokine responses in aged mice following endotoxin stress. We have begun neuromorphological analysis using unbiased stereology to count neurons, synapses, microglia and astrocytes in hippocampi of mice of different ages. Results indicate no significant age- related changes; thus, the enhanced cytokine response observed in aged mouse brain does not appear associated with glia proliferation nor were there any signficant age differences in numbers of hippocampal neurons or synapses, although the latter parameter was correlated with performance in a memory task. Regarding impaired motor performance, we have continued development of an adenoviral vector for gene transfer of the dopamine D2 receptor and confirmed that the vector can produce a functional response in rats. We are planning experiments to test in a D2 knock-out mouse.